Chemerin reverses the malignant phenotype and induces differentiation of human hepatoma SMMC7721 cells

다국어 초록 (Multilingual Abstract)

Chemerin exhibits an inhibitory eff ect on hepatocellularcarcinoma; however, the underlying mechanismis unclear. Here, low chemerin expression was confi rmedin samples of liver cancer patients and hepatoma cells.
Chemerin altered hepatoma cell morphology but had noeff ect on normal hepatocytes. Chemerin inhibited proliferationof several human hepatoma cell lines. Real-time PCRdetection of hepatocellular carcinoma markers showed thatmRNA levels of albumin and A-type gamma-glutamyltransferase increased whereas those of alpha-fetoprotein,alkaline phosphatase, B-type gamma-glutamyl transferase,insulin-like growth factor II, and human telomerase reversetranscriptase decreased in chemerin-treated SMMC7721cells. Western blotting revealed that chemerin up-regulatedalbumin and vimentin expressions, and downregulated alpha-fetoprotein expression. Phosphorylated STAT3 wassignifi cantly up-regulated, whereas phosphorylated ERKand AKT were signifi cantly downregulated by chemerin.
Chemerin decreased phosphorylated ERK and AKT expressionand the cell proliferation induced by PI3K activator 740Y-P but could not signifi cantly alter phosphorylated STAT3expression and the cell growth induced by STAT3 inhibitorNSC74859. In conclusion, chemerin reversed the malignantphenotype and induced SMMC7721 cell diff erentiation byinhibiting MAPK/ERK and PI3K/AKT signaling; growthinhibition by chemerin is not directly related to the JAK/STAT signaling pathway. Our study provides novel evidencethat chemerin could be utilized for liver cancer treatment.

참고문헌 (Reference)

1 Yuri Lazebnik, "What are the hallmarks of cancer?" Springer Science and Business Media LLC 10 (10): 232-233, 2010

2 Rourke JL, "Towards an integrative approach to understanding the role of chemerin in human health and disease" 14 : 245-262, 2013

3 Shay H, "The value of serum alkaline phosphatase determination and bromsulphalein test in the diagnosis of metastatic cancer of the liver" 43 : 741-751, 1954

4 Shanmugam Muruganandan, "The impact of bone marrow adipocytes on osteoblast and osteoclast differentiation" Wiley 66 (66): 147-155, 2014

5 Song G, "The activation of Akt/PKB signaling pathway and cell survival" 9 : 59-71, 2005

6 Sunil Nagpal, "Tazarotene-induced Gene 2 (TIG2), a Novel Retinoid-Responsive Gene in Skin" Elsevier BV 109 (109): 91-95, 1997

7 Monica Musteanu, "Stat3 Is a Negative Regulator of Intestinal Tumor Progression in ApcMin Mice" Elsevier BV 138 (138): 1003-1011.e5, 2010

8 Aggarwal BB, "Signal transducer and activator of transcription-3, infl ammation, and cancer: how intimate is the relationship?" 1171 : 59-76, 2009

9 Jongdae Lee, "Signal Transducer and Activator of Transcription 3 (STAT3) Protein Suppresses Adenoma-to-carcinoma Transition in Apc/+ Mice via Regulation of Snail-1 (SNAI) Protein Stability" Elsevier BV 287 (287): 18182-18189, 2012

10 Tsai JF, "Serum insulinlike growth factor-II as a serologic marker of small hepatocellular carcinoma" 40 : 68-75, 2005

11 Norimasa Miura, "Serum Human Telomerase Reverse Transcriptase Messenger RNA as a Novel Tumor Marker for Hepatocellular Carcinoma" American Association for Cancer Research (AACR) 11 (11): 3205-3209, 2005

12 Zeng F, "RIPK1 binds MCU to mediate induction of mitochondrial Ca2+ uptake and promotes colorectal oncogenesis" 78 : 2876-2885, 2018

13 Duvic M, "Molecular mechanisms of tazarotene action in psoriasis" 37 : 18-24, 1997

14 Singhal A, "Molecular and serum markers in hepatocellular carcinoma: predictive tools for prognosis and recurrence" 82 : 116-140, 2012

15 Chen CZ, "MicroRNAs modulate hematopoietic lineage diff erentiation" 303 : 83-86, 2004

16 Shin WJ, "Mechanisms and Functions of Chemerin in Cancer: Potential Roles in Therapeutic Intervention" 9 : 2772-, 2018

17 Weihua Jiang, "Lipin1 Regulates Skeletal Muscle Differentiation through Extracellular Signal-regulated Kinase (ERK) Activation and Cyclin D Complex-regulated Cell Cycle Withdrawal" Elsevier BV 290 (290): 23646-23655, 2015

18 Darnell JE, "Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins" 264 : 1415-1421, 1994

19 Sheen I, "Is the expression of γ -glutamyl transpeptidase messenger RNA an indicator of biological behavior in recurrent hepatocellular carcinoma" Baishideng Publishing Group Inc. 9 (9): 468-473, 2003

20 Gautam Sethi, "Inhibition of STAT3 dimerization and acetylation by garcinol suppresses the growth of human hepatocellular carcinoma in vitro and in vivo" Springer Science and Business Media LLC 13 (13): 66-, 2014

21 T G Boulton, "Identification of multiple extracellular signal-regulated kinases (ERKs) with antipeptide antibodies." American Society for Cell Biology (ASCB) 2 (2): 357-371, 1991

22 Iglesia NDI, "Identifi cation of a PTENregulated STAT3 brain tumor suppressor pathway" 22 : 449-462, 2008

23 Shi P, "IGF-IR tyrosine kinase interacts with NPM-ALK oncogene to induce survival of T-cell ALK+ anaplastic largecell lymphoma cells" 114 : 360-370, 2009

24 Raghu Kalluri, "Fibroblasts in cancer" Springer Science and Business Media LLC 6 (6): 392-401, 2006

25 McAvoy JW, "Fibroblast growth factor (FGF)induces diff erent responses in lens epithelial cells depending on its concentration" 107 : 221-228, 1989

26 ntone I, "Epigenetic programming and reprogramming during development" 20 : 282-289, 2013

27 Masayuki Matsumura, "Detection of α-fetoprotein mRNA, an indicator of hematogenous spreading hepatocellular carcinoma, in the circulation: A possible predictor of metastatic hepatocellular carcinoma" Wiley 20 (20): 1418-1425, 1994

28 Tsutsumi M, "Detection of a unique gamma-glutamyl transpeptidase messenger RNA species closely related to the development of hepatocellular carcinoma in humans: a new candidate for earlydiagnosis of hepatocellular carcinoma" 23 : 1093-1097, 1996

29 Issa ME, "Chemokine-like receptor 1 regulates skeletal muscle cell myogenesis" 302 : 1621-1631, 2012

30 Sang-gun Roh, "Chemerin—A new adipokine that modulates adipogenesis via its own receptor" Elsevier BV 362 (362): 1013-1018, 2007

31 Jing-Jing Li, "Chemerin suppresses hepatocellular carcinoma metastasis through CMKLR1-PTEN-Akt axis" Springer Science and Business Media LLC 118 (118): 1337-1348, 2018

32 Takahashi M, "Chemerin regulates β-cell function in mice" 1 : 123-, 2011

33 Huansheng Yang, "Chemerin regulates proliferation and differentiation of myoblast cells via ERK1/2 and mTOR signaling pathways" Elsevier BV 60 (60): 646-652, 2012

34 Y Lin, "Chemerin has a protective role in hepatocellular carcinoma by inhibiting the expression of IL-6 and GM-CSF and MDSC accumulation" Springer Science and Business Media LLC 36 (36): 3599-3608, 2017

35 Rebecca Siegel, "Cancer statistics, 2014" Wiley 64 (64): 9-29, 2014

36 Rosina Maria Critelli, "Biology of Hepatocellular Carcinoma" S. Karger AG 33 (33): 635-641, 2015

37 H-R Zhang, "An FGFR inhibitor converts the tumor promoting effect of TGF-β by the induction of fibroblast-associated genes of hepatoma cells" Springer Science and Business Media LLC 36 (36): 3831-3841, 2017

38 Cheung ST, "Albumin mRNA in plasma predicts post-transplant recurrence of patients with hepatocellular carcinoma" 85 : 81-87, 2008

39 Bradford MMA, "A Rapid and Sensitive Method for Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-Dye Binding" 72 : 248-254, 1976